RELIEPH for Interstitial Cystitis

美国约有790万女性和460万男性患有间质性膀胱炎/膀胱痛 综合征(IC/BPS)。对于许多患者来说，目前可用的治疗方法是不充分的，并容易 副作用，包括潜在的依赖和处方止痛药的滥用。一个 这里提出了一种创新的非药物疗法来治疗这种衰弱的疾病 IC/BPS使用新开发的名为RELIEPH(受体)的化学遗传学技术 减轻炎症引起的疼痛和多动的工程)。这项技术基于 基于与光遗传学和DREADD相同的原理，将安装工程氯离子(Cl-)通道 转化为尿路上皮细胞和外周伤害性感受器，以控制膀胱过度活动和缓解疼痛 IC/BPS。中心假说是非天然氯离子通道在神经元样中的表达 尿路上皮细胞和周围神经可以动态地重新设置外周的超敏反应 传入而不影响正常的伤害性感受过程。两种不同类型的“化学遗传” 设计将在IC/BPS的大鼠模型中进行测试。第一种类型通过感觉炎症来被动地行动。 尿路上皮细胞和神经周围组织酸中毒等情况。由于IC/BPS的病因仍未确定 未知和炎症并不总是存在，第二种类型被设计为选择性地对 小的天然化学物质(包括某些食物的代谢物)，否则几乎没有或 如果没有设计好的氯离子通道，就没有止痛作用。有希望的初步数据已经 展示了一种工程通道在治疗炎性疼痛和恢复 三项结果测量(收缩间期、最大排尿压力和排尿压力 在IC/BPS大鼠模型中)。拟议新研究的具体目标是：(1)设计 并优化由伯胺和仲胺激活或调节的配基门控氯离子通道 在普通食物中发现；(2)量化尿路上皮中工程氯离子通道的生理效应 通过检测细胞内ATP释放和细胞内钙离子的释放来进行细胞培养；(3)设计和优化有效基因 通过膀胱灌注和神经周围注射使用rAAV、脂质体和 功能化纳米颗粒，并定量表达和定位工程化受体 尿路上皮细胞和神经传入；(4)体内治疗效果和基因评价 剂量依赖，以制定改善结果的策略。 这里提出的创新想法和大胆的方法将导致根本的发展 新的IC/BPS疗法将大大有效地改善慢性疼痛的管理，并减少 处方药滥用的风险。

About 7.9 million women and 4.6 million men in the US suffer from interstitial cystitis/bladder pain syndrome (IC/BPS). For many patients, the currently available treatments are inadequate and prone to adverse side effects, including potential dependence and abuse of prescription painkillers. An innovative nonpharmacological approach is proposed here to treat the debilitating condition of IC/BPS using a newly developed chemical genetics technology called RELIEPH (Receptor Engineering to Lessen Inflammation-Evoked Pain and Hyperactivity). The technology, which is based on the same principles as optogenetics and DREADD, will install engineered chloride (Cl–) channels into urothelial cells and peripheral nociceptors to control bladder hyperactivity and to alleviate pain in IC/BPS. The central hypothesis is that the expression of non-native Cl– channels in the neuron-like urothelial cells and in peripheral nerves can dynamically re-set the hypersensitization of the peripheral afferents without affecting the process of normal nociception. Two different types of “chemical genetic” designs will be tested in a rat model of IC/BPS. The first type acts passively by sensing inflammatory conditions such as acidosis in urothelial cells and peri-nerve tissues. Since etiology of IC/BPS is still unknown and inflammation is not always present, the second type is designed to selectively respond to small natural chemicals (including metabolites of certain food) that would otherwise have little or no analgesic action without the engineered Cl– channels. Promising preliminary data have demonstrated the efficacy of one of engineered channels in treating inflammatory pain and in restoring three outcome measures (intercontraction intervals, peak micturition pressure, and micturition pressure threshold) in a rat model of IC/BPS. The specific aims for the proposed new studies are: (1) design and optimize ligand-gated Cl– channels to be activated or modulated by primary and secondary amines found in common food; (2) quantify the physiological effects of the engineered Cl– channels in urothelial cell cultures by measuring ATP release and intracellular Ca2+; (3) devise and optimize effective gene delivery strategies by bladder instillation and peri-nerve injection using rAAV, liposomes, and functionalized nanoparticles, and quantify the engineered receptor expression and localization in urothelial cells and innervating afferents; and (4) evaluate the in vivo treatment efficacies and gene dose dependence to devise strategies to improve outcomes. The innovative idea and bold approaches proposed here will lead to the development of fundamentally new IC/BPS therapy that will greatly and effectively improve chronic pain management and reduce the risk of prescription drug abuse.